Devices and methods for the treatment of cancer

ABSTRACT

The invention relates to the treatment of cancer. In particular the invention relates to an internal therapeutic product comprising: (i) an anti-cancer component selected from one or both of: a radionucleotide, a cytotoxic drug; and (ii) a silicon component selected from one or more of: resorbable silicon, biocompatible silicon, bioactive silicon, porous silicon, polycrystalline silicon, amorphous silicon, and bulk crystalline silicon, the internal therapeutic product being for the treatment of cancer.

This application is a continuation of U.S. application Ser. No.15/255,220 filed Sep. 2, 2016, which is a continuation of U.S.application Ser. No. 14/149,881 filed Jan. 8, 2014, now abandoned, whichis a continuation of U.S. application Ser. No. 13/314,239 filed Dec. 8,2011, now U.S. Pat. No. 8,647,603, which is a divisional of U.S.application Ser. No. 10/468,742 filed Aug. 22, 2003, now U.S. Pat. No.8,097,236, which is a National Phase of International Application No.PCT/GB2002/000721, filed Feb. 20, 2002, which claims priority to GB0104383.5 filed Feb. 22, 2001, the entire contents of each of which areincorporated herein by reference.

This invention relates to devices and methods for treatment of cancer,including liver cancer, kidney cancer, prostate cancer, brain cancer,and breast cancer. More specifically the invention relates to devicesand methods for the treatment of liver cancer.

Liver cancer is characterised by the growth of one or more tumours inthe lobes of the liver. Only 5% of liver cancers can be treated bysurgery. These tumours may arise directly from the liver tissue or frommetastasis from tumours in another part of the body. Metastasis ofcancer to the liver is a common cause of death for cancer patients.

Primary liver cancer is one of the most common cancers in the world. Thegreatest incidence of this disease is in Asian states where hepatitis isprevalent. The two principal causes of primary liver cancer arehepatitis B and excessive alcohol consumption.

Radiotherapy glasses have been used in the treatment of liver cancerwith beta or gamma radiation. Glasses that have been employed arebiocompatible and substantially insoluble in the body of the patient.Insolubility is considered to be an important factor, since it preventsunwanted release of the radioisotope from the target site.

An example of a radiotherapy glass, used in the treatment of livercancer, is yttrium aluminosilicate. This has been administered to theliver by injection of microparticles comprising the glass, into thehepatic artery which is the primary blood supply for target tumours. Thesize of the microparticles is such that the blood carries them into thecapillary bed of the liver, but they are too large to pass completelythrough the liver and into the circulatory system. The microparticlesfollow the flow of blood to the tumour, which has a greater than normalblood supply. The patient may benefit from a combined treatment of theliver with the microparticles together with perfusion of cytotoxic drugsinto the arterial circulation of the liver.

Unfortunately the requirement that the radioactive glass should beinsoluble may impair treatment of the cancer. The continued presence ofcancer after the isotope has decayed, may mean that further treatmentusing glass microparticles would be desirable. However, the presence ofthe, now non-radioactive, particles around the cancer reduces theeffectiveness of further treatment with radioactive particles.

A further problem, applicable to other forms of cancer treatmentinvolving the use of implantation, is the interference of the implantwith monitoring of the tumour.

When microparticles are administered into the arterial blood supply ofthe liver, it is advantageous for them to have a size, shape, anddensity that results in a relatively homogeneous distribution within theliver. If uniform distribution does not occur, then they may causeexcessive radiation in the areas of highest concentration.

There are therefore a number of factors that influence the effectivenessof treatment using radioactive microparticles. These factors includeparticle size, solubility, biocompatability, stability to radiation,density, and shape.

The use of microparticles for the treatment of liver cancer forms partof a larger field of cancer treatment in which implants are used todeliver radiation and chemotherapeutic agents. Cancers treatable in thisway also include breast cancer, kidney cancer, prostate cancer, andbrain cancer. For example radioactive seeds and pellets are presentlyused in brachytherapy of tumours, a form of therapy that involves theimplantation of a radiation source to provide localised treatment of thetumour. Brachytherapy contrasts with other methods of treatment thatinvolve treatment of a site with a radiation source that is external tothe patient's body.

It is an objective of this invention to address at least some of theabove mentioned problems.

According to a first aspect, the invention provides an internaltherapeutic product comprising:

-   -   (i) an anti-cancer component comprising at least one        radionucleotide and/or at least one cytotoxic drug; and    -   (ii) a silicon component selected from one or more of:        resorbable silicon, biocompatible silicon, bioactive silicon,        porous silicon, polycrystalline silicon, amorphous silicon, and        bulk crystalline silicon.

For the purposes of this specification bioactive silicon is silicon thatis capable of forming a bond with tissue of a patient, resorbablesilicon is silicon that is capable of resorbing in body fluid of apatient, and biocompatible silicon is silicon that is biocompatible forthe purposes of anti-cancer treatment. Certain forms of porous andpolycrystalline silicon have been found to be bioactive and/orresorbable, as disclosed in PCT/GB96/01863.

For the purposes of this specification a radionucleotide is to be takenas a radioactive nuclide. Radionucleotides are also commonly referred toas radionuclides.

The therapeutic product may comprise at least one implant. The siliconcomponent may comprise at least one implant. The or at least one of theimplants may comprise a microparticle. The therapeutic product maycomprise a suspension, suitable for injection into a patient, comprisingthe or at least one of the microparticles. The suspension may comprisean isotonic solution.

The or at least one of the implants may comprise one or more of thefollowing: a seed, a pellet, a bead. The therapeutic product maycomprise one or more of the following: a staple, a suture, a pin, aplate, a screw, a barb, coil, thread, and a nail.

The anti-cancer component may be selected from one or both of: aradionucleotide, a cytotoxic drug.

Preferably the or at least one of the implants comprises silicon and hasa shape and composition such that the or at least one of the implants issuitable for brachytherapy.

The use of silicon in the preparation of a therapeutic product for thetreatment of cancer is advantageous because silicon may readily beprocessed by standard microfabrication techniques, to form articles suchas staples, sutures, pins, plates, screws, barbs, and nails. Silicon inthe form of porous silicon may also be transmuted into radioactivecompositions, the nature of the transmutation being dependent upon thecancer to be treated.

The or at least one of the implants may comprise at least part of thesilicon component and at least part of the anti-cancer component. The orat least one of the microparticles may comprise at least part of thesilicon component and at least part of the anti-cancer component. Thetherapeutic product may comprise a multiplicity of silicon implants.

For example the internal therapeutic product may comprise a multiplicityof microparticles, each microparticle comprising porous silicon.

Preferably the largest dimension of the or at least one of themicroparticles is in the range 0.1 to 100 μm. More preferably thelargest dimension of the or at least one of the microparticles is in therange 20 to 50 μm.

If the internal therapeutic product is to be used for the treatment ofliver cancer, and is to be delivered by injecting a suspension ofmicroparticles into the hepatic artery, then the dimensions of at leastsome of the microparticles must be such that they enter, but do notexit, the liver.

Preferably the largest dimension of the or at least one of the implantsis in the range 0.01 mm to 30 mm. More preferably the largest dimensionof the or at least one of the implants is in the range 0.5 mm to 30 mm.Yet more preferably the largest dimension of the or at least one of theimplants is in the range 1 mm to 30 mm.

The largest dimension of at least one of the implants may be in therange 0.1 mm to 5 mm.

The implant may be introduced into any part of the patient's body inwhich a malignant tumour is located. For example the form of implantintroduction may be subcutaneous, intramuscular, intraperitoneal, orepidermal. The implant may be implanted into an organ such as a liver, alung, or a kidney. Alternatively the implant may be introduced intotissue consisting of vasculature or a duct.

Advantageously the specific gravity of the or at least one of theimplants is between 0.75 and 2.5 gcm⁻³, more advantageously the specificgravity of the or at least one of the implants is between 1.8 and 2.2gcm⁻³.

The use of porous silicon is advantageous in relation to the treatmentof liver cancer. This is because the density of porous silicon may becontrolled by altering its porosity. Particle density is an importantfactor in determining the success of treatment of liver cancer byadministration of microparticles to the hepatic artery.

Preferably the silicon component comprises resorbable silicon. Morepreferably the silicon component comprises resorbable silicon and theanti-cancer component comprises a radionucleotide, the radionucleotidebeing distributed through at least part of the resorbable silicon. Yetmore preferably the structure of the resorbable silicon is such that thehalf life of the radionucleotide is less than the time taken forresorbable silicon to substantially corrode when introduced into thepatient. Even more preferably the structure of the resorbable silicon issuch that the half life of the radionucleotide is less than one tenththe time taken for resorbable silicon to substantially corrode whenintroduced into the patient.

Advantageously the or at least one of the implants comprises resorbablesilicon. More advantageously the or at least one of the implantscomprises resorbable porous silicon.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than the halflife of the radionucleotide.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than twice thehalf life of the radionucleotide.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than ten timesthe half life of the radionucleotide.

By ensuring that the half life of the radionucleotide is less than thetime taken for the resorbable silicon to corrode to any significantextent, for example when it is introduced to the liver of a patient, thedanger of the radionucleotide escaping to other parts of the patient isreduced. In this way the implant may localise the radionucleotide toregion of the tumour until the radioctivity has decayed to a safe level.The use of resorbable silicon ensures that repeated administration ofthe therapeutic product is effective. Once the radionucleotide hasdecayed, or cytotoxic drug has been delivered, the therapeutic productdissolves allowing a further dose of implants (for examplemicroparticles) to be delivered to the region of the tumour. Thedissolution of the implant or implants as result of the use ofresorbable silicon also may assist in the diagnostic imaging of thepatient, since the tumour will not be masked once dissolution hasoccurred. Silicon contrasts with other resorbable materials such aspolymers, in that it is highly stable to beta and gamma radiation usedto treat liver cancer.

The silicon component may be micromachined to fabricate one or moreimplants having a predetermined size and shape, the size and/or shapebeing chosen to minimise trauma and/or swelling and/or movement of theimplant.

Advantageously the silicon component comprises porous silicon. Moreadvantageously the silicon component comprises porous silicon and theanti-cancer component comprises a cytotoxic drug, the cytotoxic drugbeing disposed in at least one of the pores of the porous silicon.

The or at least one of the implants may comprise resorbable silicon anda cytotoxic drug, the resorbable silicon having a structure andcomposition such that the implant remains sufficiently intact tosubstantially localise the drug release at the site of the implant.

The implant may be designed so that once the cytotoxic drug has beensubstantially completely released the implant is then resorbed, therebyallowing further implantation and/or diagnostic imaging of the patient.

Preferably the silicon component comprises resorbable silicon and poroussilicon, a cytotoxic drug being disposed in at least one of the pores ofthe porous silicon and a radionucleotide being distributed through atleast part of the resorbable silicon.

For example the internal therapeutic product may comprise some particlesof resorbable silicon in which a radionucleotide has been introduced,and some particles of porous silicon into which a cytotoxic drug hasbeen introduced. The internal therapeutic product may be fabricated bycombining the two types of particles, immediately prior toadministration to the patient. For example the two types of particlesmay be combined less than two hours prior to administration to thepatient.

The resorbable silicon may comprise derivatised resorbable silicon. Theporous silicon may comprise derivatised porous silicon, including thetypes of derivatised porous silicon disclosed in PCT/US99/01428 thecontents of which are herein incorporated by reference.

For the purposes of this specification derivatised porous silicon isdefined as porous silicon having a monomolecular, or monatomic layerthat is chemically bonded to at least part of the surface, including thesurface of the pores, of the porous silicon. The chemical bonding,between the layer and the silicon, may comprise a Si—C and/or Si—O—Cbonding.

The anti-cancer component may be covalently bonded to the surface of thesilicon component. The silicon component may be porous silicon, theanti-cancer component may be a radionucleotide, and the radionucleotidemay be covalently bonded to the surface of the porous silicon.

The use of porous and/or derivatised silicon is advantageous because therate of resorption can be controlled by the appropriate choice ofporosity and/or derivatisation of the silicon.

The anti-cancer component may comprise a cytotoxic drug, and thecytotoxic drug may be selected from one or more of: an alkylating agentsuch as cyclophosphamide, a cytotoxic antibody such as doxorubicin, anantimetabolite such as fluorouracil, a vinca alkaloid such asvinblastine, a hormonal regulator such as GNRH, and a platinum compoundsuch as cis platin.

The anti-cancer component may comprise a radionucleotide, and theradionucleotide may be selected from one or more of: ⁹⁰Y, ³²P, ¹²⁴Sb,¹¹⁴In, ⁵⁹Fe, ⁷⁶As, ¹⁴⁰La, ⁴⁷Ca, ¹⁰³Pd, ⁸⁹Sr, ¹³¹I, ¹²⁵I, ⁶⁰Co, ¹⁹²Ir,¹²B, ⁷¹Ge, ⁶⁴Cu, ²⁰³Pb and ¹⁹⁸Au.

The radionucleotide, such as ³²P, may be an isotope having a structureand composition that is obtainable by the transmutation of ³⁰Si. Theradionucleotide, such as ³²P, may be an isotope having a structure andcomposition that is obtainable by the transmutation of ³⁰Si, the ³⁰Siforming at least part of a sample of porous silicon. Theradionucleotide, such as ³²P, may be an isotope having a structure andcomposition that is obtainable neutron transmutation of ³⁰Si, the ³⁰Siforming at least part of a sample of porous silicon.

Preferably the internal therapeutic product comprises a porousstructure, the porous structure comprising at least part of the siliconcomponent and comprising a radionucleotide. More preferably the porousstructure comprises a radionucleotide, the structure and composition ofthe radionucleotide being obtainable by the transmutation of ³⁰Si atoms.Yet more preferably the internal therapeutic product comprises a porousstructure, the porous structure comprising at least part of the siliconcomponent and comprising a radionucleotide, the radionucleotide being³²P having a structure and composition obtainable by the transmutationof ³⁰Si atoms.

The anti-cancer component may comprise a radionucleotide, such as ⁷¹Ge,having a structure and composition that is obtainable by thetransmutation of ⁷⁰Ge. The anti-cancer component may comprise aradionucleotide, such as ⁷¹Ge, having a structure and composition thatis obtainable by the neutron transmutation of ⁷⁰Ge.

The anti-cancer component may comprise a radionucleotide, such as ⁷¹Ge,having a structure and composition that is obtainable by thetransmutation of ⁷⁰Ge atoms present in a silicon germanium alloy. Theanti-cancer component may comprise radionucleotide, such as ⁷¹Ge, thatis obtainable by the transmutation of ⁷⁰Ge atoms present in a poroussilicon germanium alloy.

The use of transmutation to fabricate the radionucleotide, from whichthe anti-cancer component is at least partly formed, may have severaladvantages. The distribution of the radionucleotide formed bytransmutation, in an implant comprising porous silicon, may besubstantially uniform. Such a uniform distribution should allowrelatively high concentrations of the radionucleotide to be introducedinto the porous silicon. Further, transmutation may allow the retentionof a porous structure, and associated biological properties, of thesilicon.

The anti-cancer component may comprise a radionucleotide and the siliconcomponent may comprise porous silicon. At least part of theradionucleotide may be distributed substantially uniformly through acubic region of porous silicon having sides greater or equal to 0.1microns. At least part of the radionucleotide may be distributedsubstantially uniformly through a cubic region of porous silicon havingsides greater or equal to 1 micron. At least part of the radionucleotidemay be distributed substantially uniformly through a cubic region ofporous silicon having sides greater or equal to 100 microns. At leastpart of the radionucleotide may be distributed substantially uniformlythrough a cubic region of porous silicon having sides greater or equalto 1000 microns.

According to a second aspect the invention provides a method of treatinga cancer, the method comprising the step of introducing an internaltherapeutic product into a patient, the internal therapeutic productcomprising:

-   -   (i) a silicon component selected from one or more of: resorbable        silicon, biocompatible silicon, bioactive silicon, porous        silicon, polycrystalline silicon, amorphous silicon, bulk        crystalline silicon; and    -   (ii) an anti-cancer component comprising at least one        radionucleotide and/or at least one cytotoxic drug.

Preferably the internal therapeutic product comprises an anti-cancercomponent selected from one or both of: a radionucleotide, a cytotoxicdrug.

Advantageously the internal therapeutic product comprises at least oneimplant, the step of introducing the internal therapeutic productcomprising the step of implanting the or at least one of the implantsinto the body of a patient. More advantageously the step of implantingthe or at least one of the implants comprises the step of biolisticallyimplanting the or at least one of the implants into organ(s) in whichthe cancer is located.

The step of implanting the or at least one of the implants may comprisethe step of implanting the or at least one of the implants into one ormore organs of the patient.

The or at least one of the implants may comprise at least part of thesilicon component and at least part of the anti-cancer component.

The or at least one of the implants may comprise resorbable silicon anda cytotoxic drug, the method of treating a cancer comprising the furtherstep of releasing at least part of the cytotoxic drug in such a mannerthat the release of the cytotoxic drug remains substantially localisedto the point of implantation.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the method of treating a cancer comprising the stepof treating part of the patient's body with radiation from theradionucleotide in such a manner that the radiation treatment islocalised to the point of implantation, and comprising the further stepof allowing the silicon to substantially completely resorb once the halflife of the radionucleotide has been exceeded.

The method of treating a cancer may be a method of brachytherapy.

Preferably the internal therapeutic product comprises a multiplicity ofmicroparticles suspended in an isotonic solution, and the step ofintroducing the internal therapeutic product comprises the step ofinjecting the suspension into an artery or vein connected to and/orlocated in organ(s) in which the cancer is located.

At least one of said microparticles may comprise at least part of thesilicon component and at least part of the anti-cancer component.

Preferably the method of treating cancer is a method of treating livercancer and the step of introducing an internal therapeutic productcomprises the step of introducing the therapeutic product into the liverof the patient.

Advantageously the internal therapeutic product comprises aradionucleotide and a cytotoxic drug and the method of treating cancercomprises the further step of combining the radionucleotide and thecytotoxic agent less than 10 hours prior the introduction of thetherapeutic product to the patient. More advantageously the step ofcombining the nucleotide and the cytotoxic agent is performed less than5 hours before the therapeutic product is introduced into the patient.Yet more advantageously the step of combining the nucleotide and thecytotoxic agent is performed less than 1 hour before the therapeuticproduct is introduced into the patient.

The cytotoxic drug may be selected from one or more of: an alkylatingagent such as cyclophosphamide, a cytotoxic antibody such asdoxorubicin, an antimetabolite such as fluorouracil, a vinca alkaloidsuch as vinblastine, a hormonal regulator such as GNRH, and a platinumcompound such as cis platin.

The radionucleotide may be selected from one or more of: ⁹⁰Y, ³²P,¹²⁴Sb, ¹¹⁴In, ⁵⁹Fe ⁷⁶As, ¹⁴⁰La, ⁴⁷Ca, ¹⁰³Pd, ⁸⁹Sr, ¹³¹I, ¹²⁵I, ⁶⁰Co,¹⁹²Ir, ¹²B, ⁷¹Ge, ⁶⁴Cu, ²⁰³Pb and ¹⁹⁸Au.

The radionucleotide, such as ³²P, may be an isotope having a structureand composition that is obtainable by the transmutation of ³⁰Si. Theradionucleotide, such as ³²P, may be an isotope having a structure andcomposition that is obtainable by the transmutation of ³⁰Si, the ³⁰Siforming at least part of a sample of porous silicon. Theradionucleotide, such as ³²P, may be an isotope having a structure andcomposition that is obtainable neutron transmutation of ³⁰Si, the ³⁰Siforming at least part of a sample of porous silicon.

Preferably the internal therapeutic product comprises a porousstructure, the porous structure comprising at least part of the siliconcomponent and comprising a radionucleotide. More preferably the porousstructure comprises a radionucleotide, the structure and composition ofthe radionucleotide being obtainable by the transmutation of ³⁰Si atoms.Yet more preferably the internal therapeutic product comprises a porousstructure, the porous structure comprising at least part of the siliconcomponent and comprising a radionucleotide, the radionucleotide being³²P having a structure and composition obtainable by the transmutationof ³⁰Si atoms.

The anti-cancer component may comprise a radionucleotide, such as ⁷¹Ge,having a structure and composition that is obtainable by thetransmutation of ⁷⁰Ge. The anti-cancer component may comprise aradionucleotide, such as ⁷¹Ge, having a structure and composition thatis obtainable by the neutron transmutation of ⁷⁰Ge.

The anti-cancer component may comprise a radionucleotide, such as ⁷¹Ge,having a structure and composition that is obtainable by thetransmutation of ⁷⁰Ge atoms present in a silicon germanium alloy. Theanti-cancer component may comprise radionucleotide, such as ⁷¹Ge, thatis obtainable by the transmutation of ⁷⁰Ge atoms present in a poroussilicon germanium alloy.

According to a third aspect, the invention provides a use of an internaltherapeutic product comprising:

-   -   (i) an anti-cancer component comprising at least one        radionucleotide and/or at least one cytotoxic drug; and    -   (ii) a silicon component selected from one or more of:        resorbable silicon, biocompatible silicon, bioactive silicon,        porous silicon, polycrystalline silicon, bulk crystalline        silicon, and amorphous silicon        for the manufacture of a medicament for the treatment of cancer.

Advantageously the internal therapeutic product comprises an anti-cancercomponent selected from one or both of: a radionucleotide, a cytotoxicdrug.

Preferably the use of an internal therapeutic product is for themanufacture of a medicament for the treatment of liver cancer.

Advantageously the use of an internal therapeutic product is for themanufacture of a medicament for the treatment of cancer bybrachytherapy.

The therapeutic product may comprise at least one implant. The or atleast one of the implants may comprise a microparticle. The therapeuticproduct may comprise a suspension, suitable for injection into apatient, comprising the or at least one of the microparticles. Thesuspension may comprise an isotonic solution.

The or at least one of the implants may comprise resorbable silicon anda cytotoxic drug, the resorbable silicon having a structure andcomposition such that the implant remains sufficiently intact tolocalise the drug release at the site of the implant.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than the halflife of the radionucleotide.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than twice thehalf life of the radionucleotide.

The or at least one of the implants may comprise resorbable silicon anda radionucleotide, the resorbable silicon having a structure andcomposition such that substantially all the radionucleotide remains inand/or on at least part of the or at least one of the implants for aperiod, measured from the time of implantation, greater than ten timesthe half life of the radionucleotide.

Preferably the largest dimension of the or at least one of the implantsis in the range 0.01 mm to 30 mm. More preferably the largest dimensionof the or at least one of the implants is in the range 0.5 mm to 30 mm.Yet more preferably the largest dimension of the or at least one of theimplants is in the range 1 mm to 30 mm.

The largest dimension of at least one of the implants may be in therange 0.1 mm to 5 mm.

The or at least one of the implants may comprise one or more of thefollowing: a seed, a pellet, a bead. The therapeutic product maycomprise one or more of the following: a staple, a suture, a pin, aplate, a screw, a barb, and a nail.

Preferably the or at least one of the implants comprises silicon and hasa shape and composition such that the or at least one of the implants issuitable for brachytherapy.

The use of silicon in the preparation of a therapeutic product for thetreatment of cancer is advantageous because silicon may readily beprocessed by standard microfabrication techniques, to form articles suchas staples, sutures, pins, plates, screws, barbs, and nails.

The or at least one of the implants may comprise at least part of thesilicon component and at least part of the anti-cancer component. The orat least one of the microparticles may comprise at least part of thesilicon component and at least part of the anti-cancer component.

Preferably the largest dimension of the or at least one of themicroparticles is in the range 0.1 to 100 μm. More preferably thelargest dimension of the or at last one of the microparticles is in therange 20 to 50 μm.

The implant may be introduced into any part of the patient's body inwhich a malignant tumour is located. For example the form of implantintroduction may be subcutaneous, intramuscular, intraperitoneal, orepidermal.

Advantageously the specific gravity of the or at least one of theimplants is between 0.75 and 2.5 gcm⁻³, more advantageously the specificgravity of the or at least one of the implants is between 1.8 and 2.2gcm⁻³.

Preferably the silicon component comprises resorbable silicon. Morepreferably the silicon component comprises resorbable silicon and theanti-cancer component comprises a radionucleotide, the radionucleotidebeing distributed through at least part of the resorbable silicon. Yetmore preferably the structure of the resorbable silicon is such that thehalf life of the radionucleotide is less than the time taken forresorbable silicon to substantially corrode when introduced into theliver of the patient. Even more preferably the structure of theresorbable silicon is such that the half life of the radionucleotide isless than one tenth the time taken for resorbable silicon tosubstantially corrode when introduced into the liver of the patient.

Preferably the silicon component comprises resorbable silicon and poroussilicon, a cytotoxic drug being disposed in at least one of the pores ofthe porous silicon and a radionucleotide being distributed through atleast part of the resorbable silicon.

The resorbable silicon may comprise derivatised resorbable silicon. Theporous silicon may comprise derivatised porous silicon.

The cytotoxic drug may be selected from one or more of: an alkylatingagent such as cyclophosphamide, a cytotoxic antibody such asdoxorubicin, an antimetabolite such as fluorouracil, a vinca alkaloidsuch as vinblastine, a hormonal regulator such as GNRH, a platinumcompound such as cis platin, and a radioactive agent.

The radionucleotide may be selected from one or more of: ⁹⁰Y, ³²P,¹²⁴Sb, ¹¹⁴In, ⁵⁹Fe ⁷⁶As, ¹⁴⁰La, ⁴⁷Ca, ¹⁰³Pd, ⁸⁹Sr, ¹³¹I, ¹²⁵I, ⁶⁰Co,¹⁹²Ir, ¹²B, ⁷¹Ge, ⁶⁴Cu, ²⁰³Pb and ¹⁹⁸Au.

For the purposes of this specification the term “patient” is either ananimal patient or a human patient.

According to a fourth aspect the invention provides a radionucleotidehaving a structure and composition obtainable by the transmutation of³⁰Si, the ³⁰Si forming at least part of a sample of porous silicon.

Preferably the readionucleotide has a structure and composition that isobtainable by neutron transmutation of ³⁰Si, the ³⁰Si forming at leastpart of a sample of porous silicon.

According to a fifth aspect the invention provides a radionucleotide,having a structure and composition obtainable by the transmutation of³⁰Si, for the treatment of cancer.

Preferably the radionucleotide has a structure and composition that isobtainable by neutron transmutation of ³⁰Si.

Advantageously the radionucleotide has a structure and composition thatis obtainable by transmutation of ³⁰Si, the ³⁰Si forming at least partof a sample of porous silicon. Advantageously the radionucleotide has astructure and composition that is obtainable by neutron transmutation of³⁰Si, the ³⁰Si forming at least part of a sample of porous silicon.

The use of the radionucleotide may be for the treatment of liver cancer.The use of the radionucleotide may be for the treatment of cancer bybrachytherapy.

According to a sixth aspect, the invention provides a method offabricating a radionucleotide comprising the step of neutron transmuting³⁰ Si, the ³⁰Si forming at least part of a sample of porous silicon.

Preferably radionucleotide is ³²P.

According to an seventh aspect, the invention provides a method offabricating an internal therapeutic comprising the step (a) oftransmuting silicon to form a radionucleotide.

Preferably radionucleotide is ³²P.

Advantageously the silicon comprises ³⁰Si.

Preferably the silicon is porous silicon. Advantageously the methodcomprises the further step (b) of porosifying the silicon. The step (b)may be performed after step (a). The step (b) may comprise the step ofanodising silicon. The step (b) may comprise the step of stain etchingsilicon.

According to a eighth aspect, the invention provides a method offabricating a radionucleotide comprising the step of neutron transmutinga porous silicon germanium alloy.

Preferably radionucleotide is ⁷¹Ge.

Advantageously the silicon germanium alloy comprises ⁷⁰Ge.

According to a ninth aspect, the invention provides a method offabricating an internal therapeutic comprising the step (a) oftransmuting a silicon germanium alloy to form a radionucleotide.

Preferably radionucleotide is ⁷¹Ge.

Advantageously the step of transmuting the silicon germanium alloycomprises the step of transmuting ⁷⁰Ge, the ⁷⁰Ge forming at least partof the silicon germanium alloy.

Advantageously the method of fabricating an internal therapeutic productcomprises the further step (b) of porosifying the silicon germaniumalloy.

The step (b) may be performed after step (a). The step (b) may comprisethe step of anodising silicon. The step (b) may comprise the step ofstain etching silicon.

According to a further aspect, the invention provides an internaltherapeutic product, as defined in any of the above aspects, for use asa medicament. According to a yet further aspect the invention provides ause of an internal therapeutic product, as defined in any of the aboveaspects, for the manufacture of a medicament for the treatment of livercancer. According to an even further aspect the invention provides a useof an internal therapeutic product, as defined in any of the aboveaspects, for the manufacture of a medicament for the treatment cancer bybrachytherapy.

The invention will now be described by way of example only.

Administration of Therapeutic Products, According to the Invention, to aPatient

Therapeutic products according to the present invention may have avariety of forms suitable for administration by subcutaneous,intramuscular, intraperitoneal, or epidermal techniques.

Therapeutic products according to the invention comprise a siliconcomponent that may be spherical, lozenge shaped, rod shaped, in the formof a strip, or cylindrical. The silicon component may form part of or atleast part of: a powder, a suspension, a colloid, an aggregate, and/or aflocculate. The therapeutic product may comprise an implant or a numberof implants, the or each implant comprising silicon and an anti-cancercomponent.

Such an implant or implants may be implanted into an organ in which atumour is located in such a manner as to optimise the therapeutic effectof the anti-cancer component.

In one aspect of the invention, the method of treatment may involvebrachytherapy, and the organ to undergo the brachytherapy may besurgically debulked and the residual space filled with the therapeuticproduct. In another aspect the organ to be treated may be cored with anarray of needles and the cores back filled with the therapeutic productof the invention, such a procedure being suitable for brachytherapy ofthe prostate.

If the therapeutic product is to be used for the treatment of livercancer, a composition may be administered to the liver by injection ofsilicon microparticles into the hepatic or celiac artery; themicroparticles being delivered in the form of a suspension in anisotonic solution such as a phosphate buffered saline solution orserum/protein based solution. The size of the microparticles is suchthat the blood carries them into, but not out of, the liver. Themicroparticles follow the flow of blood to the tumour, which has agreater than normal blood supply.

In a yet further aspect, the therapeutic product may comprise amultiplicity of porous silicon particles, said multiplicity of poroussilicon particles being divided into two types of porous siliconparticles: one type having a cytotoxic drug and no radionucleotide, anda second type having a radionucleotide and no cytotoxic drug. Both typesof particle may be administered to a patient at the same time, thoughthey may be stored separately prior to administration. In this way theproportion of the cytotoxic drug and radionucleotide may be selected tocorrespond to the condition of the patient. Separate storage of the twotypes of microparticle prior to administration to a patient may berequired if the cytotoxic agent is degraded by exposure to radiationfrom the radionucleotide.

To improve targeting further, a vasoconstricting drug such asangiotensin II may be infused prior to silicon microparticleadministration. This drug constricts the fully developed non-tumourassociated vasculature, and thereby directs the microparticles away fromnormal liver parenchyma.

Generation and/or Incorporation of the Radionucleotide

A therapeutic product according to the invention may comprise siliconcomponent and a radionucleotide. The radionucleotide may be combinedwith the silicon component, and/or it may be fabricated by thetransmutation of silicon. There are several methods by which aradionucleotide may be combined with a silicon component, or generatedby the transmutation of silicon, to form the or at least part of atherapeutic product according to the invention. Four of these methodsare given in sections (A) to (D) below.

(A) Fabrication of a ³²P Doped Porous Silicon Powder (Ai)

A standard set of CZ Si wafers, degenerately doped with phosphorous(2×10²⁰ cm⁻³) is formed into a powder by ball milling, sieving, and wetetching. The milling and sieving is carried out in such a manner thatsilicon microparticles having a largest dimension in the range 25 to 50μm are obtained. The powder is then rendered porous by stain etching inan HF based solution as described in Appl Phys Lett 64(13), 1693-1695(1994) to yield porous silicon microparticles.

Alternatively a CZ Si wafer, degenerately doped with phosphorous (2×10²⁰cm⁻³) wafer may be anodised in an HF solution, for example a 50% aqueousor ethanolic solution, to form a layer of porous silicon. Theanodisation may be carried out in an electrochemical cell by standardmethods such as that described in U.S. Pat. No. 5,348,618. For example awafer may be exposed to an anodisation current density of between 5 and500 mAcm⁻² for between 1 and 50 minutes. In this way a layer of poroussilicon having a porosities in the range 1% to 90% may be fabricated.

The porous silicon layer may then be detached from the underlying bulksubstrate by applying a sufficiently high current density in arelatively dilute electrolyte, for example a current density of greaterthan 50 mAcm⁻² for a period of 10 seconds. The detached porous siliconlayer may then be crushed to yield porous silicon particles.

Alternatively the anodised wafer may be treated ultrasonically to detachthe layer of porous silicon and to break up the layer into particles ofporous silicon. Exposure to ultrasound in this way may be performed in asolvent, the solvent being chosen to minimise agglomeration of theresulting particles. Ultrasonic treatment in this way results in theformation of porous silicon particles. Some control over particle sizes,of the porous silicon particles resulting from the ultrasonic treatment,may be achieved by centrifuging the resulting suspension to separate thedifferent particle sizes. The porous silicon particles may also be sizedby allowing the suspension to gradually settle as described in Phys.Solid State 36(8) 1294-1297 (1994).

Whether porosification is by stain etching or by anodisation, theporosity of the porous silicon may be selected so that the overalldensity of the microparticles for administration to the patient isbetween 1.5 and 2.5 gcm⁻³. The density of the porous silicon may betailored to take account of the density of the radionucleotide and orcytotoxic agent with which it is to be combined.

Silicon powders of micron particle size are available commercially andnanometre size particles can be fabricated by processes such as ballmilling, sputtering, and laser ablation of bulk silicon.

(Aii)

A sample of porous silicon particles, fabricated according to step (Ai),are subjected to thermal neutron bombardment in a nuclear reactor tobring about neutron transmutation doping of the silicon. The irradiationconditions are chosen to maximise ³²P production within the poroussilicon. In this way 10-20 mCi levels may be obtained which are suitablefor treatment of liver cancer tumours of 1 to 3 cm.

Phosphorous doping of silicon via neutron transmission doping of siliconis a well established means of producing phosphorous doped silicon atapproximately 10¹⁵ cm⁻³:

³⁰Si+n ⁰=³¹P

Further neutron capture is also possible:

³¹P+n ⁰=³²P

The amount of ³²P (a radionucleotide) present depends primarily on theamount of ³¹P produced and on the amount of P originally present, aswell as the neutron flux.

If necessary, prior to the neutron radiation described in this section,concentrations of phosphorous in porosified particles could be raised bydoping the porous silicon microparticles or particles with phosphine gasat 500 to 700 C or orthophosphoric acid followed by an anneal at 600 to1000 C. Alternatively doping of the porous silicon microparticles orparticles may be achieved by exposure to phosphorous oxychloride vapourat 800 to 900 C, as described in IEEE Electron Device Lett. 21(9), p388-390 (2000). In this way concentrations of phosphorous between 10²¹and 5×10²² cm⁻³ may be achieved.

(B) Isotope Exchange

Tritium gas is incubated with hydride passivated porous silicon. Thehydride passivated porous silicon is irradiated with an electron beam insuch a manner that the silicon-hydrogen bonds are progressively brokento allow replacement of the hydrogen with tritium. The electron beam maybe a 1-10 MeV beam. The process results in the formation of tritiatedporous silicon. A similar process of isotope exchange may also be usedfor the introduction of other radioactive gaseous species such as ¹³¹Ithat may become bonded to the internal surface of the pores. Isotopeexchange may be promoted by the application of heat and/or light and/orparticle bombardment.

(C) Ion Implantation

A sample of porous silicon may be oxidised by a low temperatureoxidation process before ion implantation of the radionucleotide bystandard techniques to fabricate a monolayer of oxide on the internalsurface of the pores. The low temperature oxidation of the poroussilicon being performed in such a manner that sintering of the poroussilicon microstructure, by the ion implantation, is prevented. The lowtemperature oxidation may be performed by heating a sample of poroussilicon at 300 C for 1 hour in substantially pure oxygen gas. The ionimplantation may be performed in such a manner that ions of theradionucleotide are implanted between 1 and 5 microns below the surfaceof the porous silicon. Acceleration voltages for ion implantation may bein the range 5 KeV to 500 KeV and ion doses may be in the range 10¹³ to10¹⁷ ion cm⁻². The temperature of the porous silicon may be maintainedat a substantially fixed temperature during ion implantation. Thetemperature of the porous silicon may be in the range −200 C to +1000 C.Examples of ions that may be ion implanted in this way are ⁹⁰Y, ¹⁴⁰La,¹²⁵I, ¹³¹I, ³²P, and ¹³⁰Pd.

(D) Liquid Infiltration

A sample of porous silicon is immersed in an aqueous solution of a saltof the radioisotope to be introduced. The salt is thermally decomposedby a first heat treatment, and the radioisotope is driven into theskeleton of the porous silicon by a second heat treatment.

Alternatively if the salt of the radioisotope has a relatively lowmelting point the salt may be melted on the surface of the poroussilicon, the molten salt being drawn into the porous silicon bycapillary action. The salt may then be thermally decomposed and driveninto the porous silicon skeleton by a two stage heating process asdescribed in WO 99/53898.

(E) Fabrication of a Radionucleotide by Transmutation of a SiliconGermanium Alloy (Ei)

A boron-doped polycrystalline silicon germanium bulk alloy may be grownby oriented crystallisation within a crucible using standard techniquessuch as the Polix method. The alloy may be fabricated in such a mannerthat the alloy comprises 1-15 at % Ge and has a resistivity of 1 to 0.01ohm cm. The resulting ingot of the alloy may be mechanically sawn intosheets having thickness 200 to 500 microns, which may then be subjectedto a wet polish etch to remove saw damage. Anodisation may then beperformed at current densities in the range 5 to 500 mAcm⁻² in HF basedelectrolytes for periods between 5 minutes and 5 hours.

The resulting layer of porous Silicon germanium may then be converted toa powder of porous silicon germanium particles by similar methods tothose described in section Ai.

The porous Silicon germanium powder may then be subjected to particlebombardment, for example neutron bombardment, to transmute ⁷⁰Ge to theradionucleotide ⁷¹Ge.

Alternatively a standard Si or SOI wafer may be coated with acrystalline Si_(x)Ge_((1-x)) layer, or with alternate ultrathin layersof crystalline silicon and germanium. The Si and Ge being fabricatedfrom silane and germane by standard CVD techniques. The CVD depositiontemperature may be in the range 300K to 1000K. For situations in which asilicon substrate is used porosification of the silicon germanium alloymay be by anodisation or by stain etching. For situations in which a SOIsubstrate is used, stain etching may be used to both porosify and detachthe silicon alloy from the substrate.

Formation of the porous silicon alloy powder and transmutation is thenperfomred in a similar manner as that described in (Ei).

Fabrication of Porous Silicon Implants having a Well Defined Shape andWell Defined Dimensions

A first Si wafer, having a sacrificial organic film applied to onesurface, is etched using standard MEMS processing to form a first arrayof photolithographically defined objects. If the entire Si waferthickness is etched through, then the first array is held in place bythe sacrificial organic film. The first array is then bonded to a secondelectrically conductive wafer in preparation for subsequent anodisation.The second wafer may be silicon having the same conductivity type anddifferent resistivity, or a metal coated silicon wafer having the sameconductivity type and same resistivity as the first silicon wafer. Thefirst array is then treated with solvent to remove the organic film.Anodisation in HF based electrolyte is then performed until the firstarray is completely porosified. Incorporation of the radioisotope maythen be performed by treatment of the first array in powder form, or bytreatment of the first array while bonded to the second wafer.

A similar process for the preparation of a second array of poroussilicon photolithographically defined objects may also be performed byetching a SOI wafer by standard MEMS processing.

Combination of Silicon Microparticles with Cytotoxic Agent

The porous silicon microparticles, fabricated either by step (Ai) aloneor by step (Ai) in combination with step (Aii), are then impregnatedwith a cytotoxic drug used for treating liver cancer, such as5-fluorouracil.

There are a number of methods by which a cytotoxic drug may beassociated with the microparticle. The cytotoxic drug may be dissolvedor suspended in a suitable solvent, the microparticles may then beincubated in the resulting solution for a period of time. The cytotoxicdrug may then be deposited on the surface of the microparticles. If themicroparticles comprise porous silicon, then a solution of the cytotoxicdrug may be introduced into the pores of the porous silicon by capillaryaction. Similarly if the microparticles have a cavity then the solutionmay also be introduced into the cavity by capillary action. If thecytotoxic drug is a solid but has a sufficiently high vapour pressure at20 C then it may be sublimed onto the surface of the microparticles. Ifa solution or suspension of the cytotoxic drug can be formed then thesubstance may be applied to the microparticles by successive immersionin the solution/suspension followed by freeze drying.

A further method by which a cytotoxic drug may be associated with poroussilicon is through the use of derivatised porous silicon. The cytotoxicdrug may be covalently attached directly to the derivatised silicon by aSi—C or Si—O—C bond. The release of the cytotoxic agent is achievedthrough biodegradation of the porous silicon.

1-14. (canceled)
 15. An internal therapeutic product comprising: (i) ananti-cancer component comprising at least one radionucleotide and/or atleast one cytotoxic drug; and (ii) a silicon component selected from oneor more of: resorbable silicon, biocompatible silicon, bioactivesilicon, porous silicon, polycrystalline silicon, amorphous silicon, andbulk crystalline silicon.
 16. An internal therapeutic product accordingto claim 15, wherein therapeutic product comprises at least one implant.17. An internal therapeutic product according to claim 16, wherein theor at least one is of the implants comprises at least part of thesilicon component and at least part of the anti-cancer component.
 18. Aninternal therapeutic product according to claim 15, wherein the siliconcomponent comprises resorbable silicon.
 19. An internal therapeuticproduct according to claim 15, wherein the silicon component comprisesresorbable silicon and the anti-cancer component comprises aradionucleotide, the radionucleotide being distributed through at leastpart of the resorbable silicon.
 20. An internal therapeutic productaccording to claim 17, wherein the or at least one of the implantscomprises resorbable silicon and a radionucleotide, the resorbablesilicon having a structure and composition such that substantially allthe radionucleotide remains in and/or on at least part of the or atleast one of the implants for a period, measured from the time ofimplantation, greater than the half life of the radionucleotide.
 21. Aninternal therapeutic product according to claim 17, wherein the or atleast one of the implants may comprise resorbable silicon and acytotoxic drug, the resorbable silicon having a structure andcomposition such that the implant remains sufficiently intact tosubstantially localise the drug release at the site of the implant. 22.An internal therapeutic product according to claim 1, whereinanti-cancer agent comprises a radionucleotide, and the radionucleotideis selected from one or more of: ⁹⁰Y, ³²P, ¹²⁴Sb, ¹¹⁴In, ⁵⁹Fe, ⁷⁶As,¹⁴⁰La, ⁴⁷Ca, ¹⁰³Pd, ⁸⁹Sr, ¹³¹I, ¹²⁵I, ⁶⁰Co, ¹⁹²Ir, and ¹⁹⁸Au.
 23. Amethod of treating a cancer, the method comprising the step ofintroducing an internal therapeutic product into a patient, the internaltherapeutic product comprising: (i) a silicon component selected fromone or more of: resorbable silicon, biocompatible silicon, bioactivesilicon, porous silicon, polycrystalline silicon, amorphous silicon,bulk crystalline silicon; and (ii) an anti-cancer component comprises atleast one radionucleotide and/or at least one cytotoxic drug.
 24. Amethod according to claim 23, wherein the internal therapeutic productcomprises at least one implant, the step of introducing the internaltherapeutic product comprising the step of implanting the or at leastone of the implants into the body of a patient.
 25. A method accordingto claim 24, wherein the or at least one of the implants comprises atleast part of the silicon component and at least part of the anti-cancercomponent.
 26. A method according to claim 25, wherein the or at leastone of the implants comprises resorbable silicon and a cytotoxic drug,the method of treating a cancer comprising the further step of releasingat least part of the cytotoxic drug in such a manner that the release ofthe cytotoxic drug remains substantially localised to the point ofimplantation.
 27. A method according to claim 25, wherein the or atleast one of the implants comprises resorbable silicon and aradionucleotide, the method of treating a cancer comprising the step oftreating part of the patient's body with radiation from theradionucleotide in such a manner that the radiation treatment islocalised to the point of implantation, and comprising the further stepof allowing the silicon to substantially completely resorb once the halflife of the radionucleotide has been exceeded.
 28. A method according toclaim 23, wherein the internal therapeutic product comprises aradionucleotide and a cytotoxic drug and the method of is treatingcancer comprises the further step of combining the radionucleotide andthe cytotoxic agent less than 10 hours prior the introduction of thetherapeutic product to the patient.
 29. An internal therapeutic productaccording to claim 15, wherein the anti-cancer component comprise aradionucleotide having a structure and composition obtainable by thetransmutation of porous silicon.
 30. An internal therapeutic productaccording to claim 15, wherein the anti-cancer component comprise aradionucleotide having a structure and composition obtainable by thetransmutation of germanium atoms that form part of a porous silicongermanium alloy.